Retatrutide for Knee Osteoarthritis: The TRIUMPH-4 Results

The TRIUMPH-4 Phase 3 trial, announced by Eli Lilly on December 11, 2025, is the first Phase 3 trial for retatrutide to report results. It was designed to evaluate retatrutide in adults with both obesity and knee osteoarthritis — two conditions that are deeply intertwined. The results were striking: weight loss of up to 28.7%, knee pain reduction of up to 75.8%, and approximately 1 in 7 participants on the 9mg dose becoming completely pain-free.

Osteoarthritis of the knee is the most common form of arthritis and a leading cause of disability worldwide. Obesity is one of its strongest modifiable risk factors — every pound of body weight translates to approximately 4 pounds of pressure on the knee joint. Weight loss has long been recommended as a first-line intervention, but achieving the magnitude of weight loss needed to meaningfully reduce symptoms has been difficult without surgery.

Retatrutide is an investigational drug that has not been approved by the FDA.

TRIUMPH-4 Trial Design

Baseline characteristics

• Mean body weight: 112.7 kg
• Mean BMI: 40.4
• 84% had BMI of 35 or higher (Class 2 or 3 obesity)
• Mean baseline WOMAC pain score: 6.0 points (on a 0-10 scale)

The WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) is the standard validated instrument for measuring osteoarthritis symptoms. It assesses pain, stiffness, and physical function. The baseline pain score of 6.0 indicates moderate-to-severe knee pain.

Weight Loss Results

The 28.7% mean weight loss at 12mg over 68 weeks is the largest reported in any Phase 3 obesity trial to date. It confirms and extends the Phase 2 results (which showed up to 24.2% at 48 weeks), demonstrating that weight loss continues to progress between 48 and 68 weeks at the higher doses.

Knee Pain and Physical Function Results

WOMAC pain score

Both doses produced substantial pain improvement relative to placebo. Notably, the placebo group also showed meaningful improvement (40.3% pain reduction), which is common in osteoarthritis trials due to the natural fluctuation of symptoms and the placebo effect. However, the active treatment groups achieved roughly double the pain reduction of placebo.

Complete pain resolution

• 14.1% of 9mg participants and 12.0% of 12mg participants were completely free of knee pain at 68 weeks
• This compared to 4.2% on placebo
• Complete pain resolution is a high bar — it represents the elimination of all knee osteoarthritis pain, not merely an improvement

WOMAC physical function

Physical function improvements paralleled the pain reductions, indicating that the benefits translated to real-world ability to perform daily activities — walking, climbing stairs, standing, and bending.

Cardiovascular and Metabolic Improvements

TRIUMPH-4 also measured cardiometabolic markers, all of which improved significantly in the retatrutide groups:

The 14.0 mmHg reduction in systolic blood pressure is clinically meaningful — it approaches the effect size of some antihypertensive medications. The improvement in hsCRP (high-sensitivity C-reactive protein) is noteworthy because it is a marker of systemic inflammation, which is relevant to both cardiovascular disease and the inflammatory component of osteoarthritis.

How Weight Loss Affects Knee Osteoarthritis

The mechanism by which retatrutide improves knee osteoarthritis is primarily through weight loss. The relationship between obesity and knee osteoarthritis is both mechanical and metabolic:

Mechanical load

• Each pound of body weight translates to approximately 4 pounds of force on the knee joint during walking
• A person who loses 70 lbs (as achieved at the 12mg dose) reduces the load on their knee by approximately 280 lbs per step
• This reduction in mechanical stress decreases cartilage breakdown, reduces pain, and improves joint function

Systemic inflammation

• Obesity is associated with chronic low-grade inflammation, driven by adipose tissue (fat cells) secreting pro-inflammatory cytokines
• These inflammatory mediators contribute to cartilage degradation and joint pain beyond what mechanical loading alone explains
• Weight loss reduces adipose tissue-derived inflammation, as reflected in the hsCRP improvements seen in TRIUMPH-4

Why the 9mg and 12mg results were similar for pain

An interesting finding in TRIUMPH-4 was that the 9mg and 12mg doses produced very similar pain outcomes (75.8% vs. 74.3%) despite different weight loss (26.4% vs. 28.7%). This suggests that beyond a certain threshold of weight loss — perhaps around 25-26% — additional weight loss provides diminishing returns for joint pain relief. The mechanical offloading and anti-inflammatory effects may have reached a near-maximum benefit at the 9mg dose.

Safety and Adverse Events

The adverse event profile in TRIUMPH-4 was consistent with the GLP-1 drug class:

Discontinuation rates: 12.2% at 9mg, 18.2% at 12mg, and 4.0% for placebo. Eli Lilly noted that some discontinuations at higher doses were attributed to "perceived excessive weight loss" rather than intolerable side effects.

Dysesthesia (abnormal sensations such as tingling, burning, or numbness) was a new safety signal in this trial, particularly at the 12mg dose (20.9%). For detailed analysis of safety data, see Retatrutide Side Effects & Safety.

What This Means for Osteoarthritis Treatment

A potential new paradigm

Currently, the treatment options for obesity-related knee osteoarthritis are limited:

• Lifestyle modification — effective but difficult to sustain at the required magnitude
• Physical therapy — improves function and pain but does not address the root cause of excess weight
• NSAIDs and analgesics — symptom management only, with their own side effect risks
• Corticosteroid or hyaluronic acid injections — temporary relief
• Knee replacement surgery — effective but invasive, costly, and often deferred in younger patients

A drug that simultaneously addresses the root cause (obesity) and produces substantial symptom relief could reshape treatment algorithms for obesity-related osteoarthritis.

Regulatory implications

Eli Lilly has stated it plans to include the TRIUMPH-4 osteoarthritis data in its regulatory submissions. If approved, retatrutide could receive a specific indication for weight management in adults with obesity and knee osteoarthritis — similar to how Zepbound received an OSA indication.

TRIUMPH-4 was designed with two co-primary endpoints to support both a weight-management indication and a pain-relief indication for knee osteoarthritis. Both were met — opening a path to two regulatory filings from a single trial.

What Comes Next

• Full peer-reviewed publication of TRIUMPH-4 is expected with additional secondary endpoints and body composition data.
• Combined with TRIUMPH-3 (Mar 2026) and TRANSCEND-T2D-1 (Mar 2026), three of the major retatrutide Phase 3 trials have now reported.
• TRIUMPH-1 and TRIUMPH-2 — the larger obesity-population trials — are still expected to read out in 2026.
• FDA filing is expected in 2026 per Lilly guidance, supporting obesity, knee OA, OSA, and potentially type 2 diabetes indications. See our FDA approval timeline.

Frequently Asked Questions

Sources

• Eli Lilly and Company. (2025). Lilly's retatrutide achieved significant weight loss and pain relief in adults with obesity and knee osteoarthritis. Press release.
• ClinicalTrials.gov: NCT05931367
• Messier, S.P., et al. (2004). Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis. Arthritis & Rheumatism.